INJECTABLE LONG-ACTING IVACAFTOR-LOADED POLY (LACTIDE-CO-GLYCOLIDE) MICROPARTICLE FORMULATIONS FOR THE TREATMENT OF CYSTIC FIBROSIS: IN VITRO CHARACTERIZATION AND IN VIVO PHARMACOKINETICS IN MICE

David S Nakhla; Aml I Mekkawy; Youssef W Naguib; Aaron D Silva; Dylan Gao; Jeong Ah Kim; Suhaila O Alhaj-Suliman; Timothy M Acri; Krishna Kumar Patel; Sarah Ernst; David A Stoltz; Michael J Welsh; Aliasger K Salem

doi:10.1016/j.ijpharm.2023.123693

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INJECTABLE LONG-ACTING IVACAFTOR-LOADED POLY (LACTIDE-CO-GLYCOLIDE) MICROPARTICLE FORMULATIONS FOR THE TREATMENT OF CYSTIC FIBROSIS: IN VITRO CHARACTERIZATION AND IN VIVO PHARMACOKINETICS IN MICE

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INJECTABLE LONG-ACTING IVACAFTOR-LOADED POLY (LACTIDE-CO-GLYCOLIDE) MICROPARTICLE FORMULATIONS FOR THE TREATMENT OF CYSTIC FIBROSIS: IN VITRO CHARACTERIZATION AND IN VIVO PHARMACOKINETICS IN MICE

David S Nakhla, Aml I Mekkawy, Youssef W Naguib, Aaron D Silva, Dylan Gao, Jeong Ah Kim, Suhaila O Alhaj-Suliman, Timothy M Acri, Krishna Kumar Patel, Sarah Ernst, …

International journal of pharmaceutics, Vol.650, 123693

01/2024

DOI: 10.1016/j.ijpharm.2023.123693

PMCID: PMC10843602

PMID: 38081555

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Abstract

Optimizing a sustained-release drug delivery system for the treatment of cystic fibrosis is crucial for decreasing the dosing frequency and improving patients' compliance with the treatment regimen. In the current work, we developed an injectable PLGA microparticle formulation loaded with ivacaftor, a CFTR potentiator that increases the open probability of the CFTR anion channel, using a single emulsion solvent evaporation technique. We aimed to study the effect of different parameters on the characteristics of the prepared formulations to select an optimized microparticle formulation to be used in the in vivo pharmacokinetic study in mice. First, ivacaftor-loaded microparticles were prepared while varying the formulation parameters to study their effect on the formulations' size, morphology, drug loading, encapsulation efficiency, and in vitro release profiles. All the prepared microparticles showed smooth spherical surfaces with internal diameters of 1.91- 6.93 µm, drug loading (DL) of 3.91 - 10.3%, percent encapsulation efficiencies (%EE) of 26.6 - 100%, and an overall slow cumulative release profile. We selected one formulation that showed the best combined %DL and %EE values (8.25, and 90.7%, respectively), with an average particle size of 6.83 µm, and a slow bi-phasic in vitro release profile (up to 6 weeks) to study its in vivo pharmacokinetics in comparison to solubilized ivacaftor following their subcutaneous (SC) and intravenous (IV) administration to mice, respectively. The injected microparticle formulation showed steady plasma levels of ivacaftor over a period of 28 days, and a 6-fold increase in AUC (71.6 µg/mL*h) compared to the intravenously injected soluble ivacaftor (12.3 µg/mL*h). Our results suggest that this novel ivacaftor-loaded microparticle formulation could potentially eliminate the need for the frequent daily administration of ivacaftor by people with cystic fibrosis which could improve their compliance and ensure successful treatment outcomes.

Cystic Fibrosis

Pharmacokinetics

PLGA microparticles

long-acting injectables (LAI)

ivacaftor

Details

Title: Subtitle: INJECTABLE LONG-ACTING IVACAFTOR-LOADED POLY (LACTIDE-CO-GLYCOLIDE) MICROPARTICLE FORMULATIONS FOR THE TREATMENT OF CYSTIC FIBROSIS: IN VITRO CHARACTERIZATION AND IN VIVO PHARMACOKINETICS IN MICE
Creators: David S Nakhla - University of Iowa
Aml I Mekkawy
Youssef W Naguib - University of Iowa
Aaron D Silva - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA
Dylan Gao - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA
Jeong Ah Kim - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA
Suhaila O Alhaj-Suliman - University of Iowa
Timothy M Acri - University of Iowa
Krishna Kumar Patel - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA
Sarah Ernst
David A Stoltz
Michael J Welsh
Aliasger K Salem
Resource Type: Journal article
Publication Details: International journal of pharmaceutics, Vol.650, 123693
DOI: 10.1016/j.ijpharm.2023.123693
PMID: 38081555
PMCID: PMC10843602
NLM abbreviation: Int J Pharm
eISSN: 1873-3476
Grant note: DOI: 10.13039/100000011, name: Howard Hughes Medical Institute; DOI: 10.13039/100000002, name: National Institutes of Health, award: P30CA086862
Language: English
Electronic publication date: 12/09/2023
Date published: 01/2024
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Dental Research; Chemical and Biochemical Engineering; Neurosurgery; Internal Medicine
Record Identifier: 9984530282702771

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